Controlled release hydrocodone formulations

ABSTRACT

A solid oral controlled-release oral dosage form of hydrocodone is disclosed. The dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a sufficient amount of a controlled release material to render the dosage form suitable for twice-a-day administration to a human patient, the dosage form providing a C12/Cmax ratio of 0.55 to 0.85, said dosage form providing a therapeutic effect for at least about 12 hours.

This application is a continuation of U.S. Ser. No. 12/982,386, filed onDec. 30, 2010, which is a continuation of U.S. Ser. No. 10/864,829,filed on Jun. 9, 2004, now U.S. Pat. No. 7,943,174, which is acontinuation of U.S. Ser. No. 09/702,283, filed on Oct. 30, 2000, whichclaims priority from U.S. Provisional Application Ser. No. 60/162,541filed Oct. 29, 1999, all hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Due to the difficulties presented by the pharmacotherapy of pain,particularly chronic pain, opioid analgesics are ideal drugs to beadministered as controlled release formulations. The present inventionrelates to a solid, controlled-release oral dosage form for use in thetreatment of pain.

It is the intent of all controlled (slow) release formulations toprovide a longer period of pharmacological action after administrationthan is ordinarily obtained after administration of immediate-releasedosage forms. Such longer periods of response provide for manytherapeutic benefits that are not achieved with corresponding shortacting, immediate release preparations. Thus, therapy may be continuedwithout interrupting the sleep of the patient, which is of specialimportance, for example, when treating a patient for moderate to severepain (e.g., a post-surgery patient, a cancer patient, etc.), or forthose patients who experience migraine headaches on awakening, as wellas for the debilitated patient for whom sleep is essential.

Unless conventional rapid acting drug therapy is carefully administeredat frequent intervals to maintain effective steady state plasmaconcentrations of the drug, peaks and valleys in the plasma level of theactive drug occurs because of the rapid absorption, systemic excretionof the compound and through metabolic inactivation, thereby producingspecial problems in maintenance therapy of the patient. A furthergeneral advantage of longer acting drug preparations is improved patientcompliance resulting from the avoidance of missed doses through patientforgetfulness.

It is known in the pharmaceutical art to prepare compositions whichprovide for controlled release of pharmacologically active substancescontained in the compositions after oral administration to humans andanimals. Such slow release compositions are used to delay absorption ofa medicament until it has reached certain portions of the alimentarytract. Such controlled release of a medicament in the alimentary tractfurther maintains a desired concentration of said medicament in theblood stream for a longer duration than would occur if conventionalrapid release dosage forms are administered.

The prior art teaching of the preparation and use of compositionsproviding the controlled release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiologic fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, ensure bioavailability.

In order to be absorbed, the active drug substance must be in solution.The time required for a given proportion of an active substance from aunit dosage form is determined as the proportion of the amount of activedrug substance released from a unit dosage form over a specified timebase by a test method conducted under standardized conditions. Thephysiologic fluids of the gastrointestinal tract are the media fordetermining dissolution time. The present state of the art recognizesmany satisfactory test procedures to measure dissolution time forpharmaceutical compositions, and these test procedures are described inofficial compendia worldwide.

Although there are many diverse factors which influence the dissolutionof a drug substance from its carrier, the dissolution time determinedfor a pharmacologically active substance from the specific compositionis relatively constant and reproducible. Among the different factorswhich may affect the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified in itssteady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologic conditions,the saturation level of the dissolved materials is replenished from thedosage form reserve to maintain a relatively uniform and constantdissolution concentration in the solvent medium providing for a steadystate absorption.

The transport across a tissue absorption site of the gastrointestinaltract is influenced by the Donnan osmotic equilibrium forces on bothsides of the membrane since the direction of the driving force is thedifference between the concentrations of active substance on either sideof the membrane, i.e., the amount dissolved in the gastrointestinalfluids and the amount present in the blood. Since the bloodconcentrations are constantly being modified by dilution, circulatorychanges, tissue storage, metabolic conversion and systemic excretion,the flow of active materials is directed from the gastrointestinal tractinto the blood stream.

Various techniques have been used to prepare controlled release dosageforms. Specially coated pellets, tablets and capsules wherein the slowrelease of the active medicament is brought about through selectivebreakdown of the coating of the preparation or through compounding witha special matrix to affect the release of a drug are known in the art.Certain controlled release formulations provide for related sequentialrelease of a single dose of an active compound at predetermined periodsafter administration.

Specific examples of controlled release opioid formulations reported inthe patent literature include, for example, those disclosed in U.S. Pat.Nos. 4,990,341 and 4,844,909 (Goldie, et al.), both assigned to theassignee of the present invention and incorporated herein by reference,describe hydromorphone compositions wherein the dissolution ratein-vitro of the dosage form, when measured by the USP Paddle or BasketMethod at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at37° C., is between 12.5 and 42.5% (by wt) hydromorphone released after 1hour, between 25 and 55% (by wt) released after 2 hours, between 45 and75% (by wt) released after 4 hours and between 55 and 85% (by wt)released after 6 hours, the in-vitro release rate being independent ofpH between pH 1.6 and 7.2 and chosen such that the peak plasmaconcentration of hydromorphone obtained in-vivo occurs between 2 and 4hours after administration of the dosage form. At least 12 hours of painrelief is obtained with these hydromorphone formulations.

It is considered highly desirable to provide controlled-release dosageformulations of other opioid analgesic drugs which can be used formoderate pain. It is further considered highly desirable to provide suchcontrolled-release formulations with pharmacokinetic properties whichprovide the most effective pain management in patients in need of paintherapy.

SUMMARY OF THE INVENTION

It is an object of the present invention to substantially improve theefficiency and quality of pain management in human patients experiencingmoderate pain.

It is an object of the present invention to provide bioavailablehydrocodone formulations that substantially improve the efficiency andquality of pain management.

It is yet another object of the present invention to providebioavailable controlled-release hydrocodone formulations which provide asubstantially increased duration of effect as compared to immediaterelease hydrocodone formulations, but which provide an early onset ofanalgesia.

It is a further object of the invention to provide orally administrablecontrolled release opioid formulations suitable for twice-a-dayadministration which provide an early onset of therapeutic effect andwhich, after rising to a maximum concentration during the dosageinterval, provide a relatively flat serum plasma profile, meaning thatthe plasma level of the opioid provides a C₁₂/C_(max) ratio of 0.55 to0.85, and which provides effective pain relief to the patient. Inalternate embodiments, the dosage form provides a C₁₂/C_(max) ratio of0.65 to 0.75

The above objects and others are attained by virtue of the presentinvention, which in certain embodiments, provides a solid oralcontrolled-release dosage form comprising an analgesically effectiveamount of hydrocodone or a pharmaceutically acceptable salt thereof anda sufficient amount of a controlled release material to render thedosage form suitable for twice-a-day administration, the dosage formafter single administration to a human patient or a population ofpatients, providing a time to peak plasma concentration of hydrocodonein-vivo, preferably at from about 2 to about 8 hours (Tmax), and afterattaining a maximum concentration, providing a C₁₂/C_(max) ratio of 0.55to 0.85.

In certain preferred embodiments, the controlled release dosage formprovides an in-vitro release of from 18% to about 42.5% by weight of thehydrocodone or salt thereof from the dosage form at one hour whenmeasured by the USP Basket Method at 100 rpm in 700 ml of SimulatedGastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to900 ml of Simulated Intestinal Fluid (SIF) at 37° C.

In certain preferred embodiments, the dissolution rate in-vitro of thehydrocodone dosage form when measured by the USP Basket method at 100rpm in 900 ml aqueous buffer at a pH of 1.2 and 7.5 at 37° C. is fromabout 25 to about 65% by weight of the hydrocodone or salt thereofreleased after 2 hours, from about 45 to about 85% by weight of thehydrocodone or salt thereof released after 4 hours, and greater thanabout 60% by weight of the hydrocodone or salt thereof released after 8hours. Although the in-vitro release rate may be either pH-independentor pH-dependent as desired, in preferred embodiments of the inventionthe release of hydrocodone is pH-independent.

In certain preferred embodiments, there is provided a controlled releasedosage form comprising a therapeutically effective amount of hydrocodonewherein the dosage form provides a hydrocodone plasma concentration ofat least 5 or 6 ng/ml, at 12 hours after administration and provides aplasma concentration of at least about 8 ng/ml at from about 2 to about8 hours after administration.

In other preferred embodiments of the invention, there is provided atwice-a-day oral controlled release dosage form of hydrocodone whichprovides a Cmax of hydrocodone which is less than about 50% of the Cmaxof an equivalent dose of an immediate release hydrocodone referenceformulation (e.g. Lortab®), and which provides effective analgesiaduring the 12 hour dosage interval.

In other preferred embodiments of the invention, there is provided atwice-a-day controlled release dosage form of hydrocodone wherein thedosage form provides a time to 80% Cmax which is from about 90% to about150%, preferably from about 90% to about 110%, of the time to 80% Cmaxof an equivalent dose of immediate release hydrocodone referenceformulation (e.g. Lortab). Preferably, the time to 80% Cmax ofhydrocodone for the controlled release dosage form being from about 0.5to about 1.5 hours, most preferably from about 0.8 to about 1.2 hours.In alternate embodiments, the time to 80% Cmax of hydrocodone for thecontrolled release dosage form is from about 0.75 to about 2.0 hours,most preferably from about 0.9 to about 1.5 hours.

In other preferred embodiments of the invention, there is provided atwice-a-day controlled release dosage form of hydrocodone wherein thedosage form provides a time to 90% Cmax which is about 150% to about400%, preferably from about 150% to about 250%, of the time to 90% Cmaxof an equivalent dose of immediate release hydrocodone referenceformulation. Preferably, the time to 90% Cmax of hydrocodone for thecontrolled release dosage form is from about 1.5 to about 2.5 hours,most preferably from about 1.8 to about 2.2 hours. In alternateembodiments, the time to 90% Cmax of hydrocodone for the controlledrelease dosage form is from about 1.5 to about 4.0 hours, mostpreferably from about 1.8 to about 2.5 hours.

In other preferred embodiments of the invention, there is provided atwice-a-day controlled release dosage form of hydrocodone wherein thedosage form maintains a plasma concentration within 80% of Cmax fromabout 0.5 to 10 hours, preferably from about 1 to about 9 hours or fromabout 4 to about 8 hours.

In other preferred embodiments of the invention, there is provided atwice-a-day controlled release dosage form of hydrocodone whichmaintains a plasma plasma concentration of hydrocodone within 90% ofCmax from about 1 to 6.5 hours, preferably from about 2 to about 5 hoursor from about 2 to about 6.5 hours.

In other preferred embodiments of the invention, there is provided atwice-a-day controlled release dosage form of hydrocodone which providesa mean in-vivo absorption rate from administration to Tmax from about1.5 mg/hour to about 5 mg/hour and provides a mean rate of absorptionfrom Tmax to the end of the dosing interval which is less than about 0.5mg/hour based on oral administration of a dosage form containing 15 mghydrocodone bitartrate. Preferably, the dosage form provides a meanin-vivo absorption rate from administration to Tmax from about 2 mg/hourto about 4 mg/hour and provides a mean in-vivo absorption rate Tmax tothe end of the 12 hour dosing interval which is from about 0.08 mg/hourto about 0.4 mg/hour based on oral administration of a dosage formcontaining 15 mg hydrocodone bitartrate.

In other preferred embodiments of the invention, there is provided atwice-a-day oral controlled release hydrocodone dosage form whichprovides a rate of absorption during the time period from Tmax to about12 hours after oral administration of the dosage form which is fromabout 55% to about 85% of the rate of elimination during the same timeperiod.

The above embodiments of the invention, as well as other embodiments,preferably provide a time to Tmax at a time point 3 to 4 times laterthan the Tmax provided by an equivalent dose of an immediate releasehydrocodone reference. Preferably, the Tmax provided by the sustainedrelease formulation occurs at from about 2 to about 8 hours, from about3 to about 7 hours or from about 4 to about 6 hours after oraladministration.

The present invention is further directed to hydrocodone formulationswhich provide a Cmax of hydrocodone which is less than about 50%,preferably less than about 40% of the Cmax provided by an equivalentdose of an immediate release reference product.

For example, it was surprisingly discovered that when hydrocodone isformulated in the delivery system as disclosed in U.S. Pat. Nos.4,861,598 and 4,970,075, the Cmax of hydrocodone provided by thedelivery system as a percentage of the Cmax of an immediate releasereference product was considerably lower than the same calculation foroxycodone formulated in the same delivery system. This phenomena isevident, regardless of the fact that the controlled release oxycodoneand hydrocodone formulations exhibited similar in-vitro dissolutionparameters.

When the present invention is formulated using the delivery systems U.S.Pat. Nos. 4,861,598 and 4,970,075, the Cmax of the delivery system as apercentage of the Cmax of the immediate release reference product isless than about 50%, and less than 40% in preferred embodiments, whereasoxycodone, exhibits a calculation of greater than 50%.

“Hydrocodone” is defined for purposes of the invention as includinghydrocodone free base, as well as pharmaceutically acceptable salts andcomplexes of hydrocodone.

The term “USP Paddle or Basket Method” is the Paddle and Basket Methoddescribed, e.g., in U.S. Pharmacopoeia XXII (1990), herein incorporatedby reference.

The term “pH-dependent” for purposes of the present invention is definedas having characteristics (e.g. dissolution) which vary according toenvironmental pH.

The term “pH-independent” for purposes of the present invention isdefined as having characteristics (e.g., dissolution) which aresubstantially unaffected by pH.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., hydrocodone) isabsorbed from the unit dosage forms.

The term “controlled-release” is defined for purposes of the presentinvention as the release of the drug (e.g., hydrocodone) at such a ratethat blood (e.g., plasma) concentrations are maintained within thetherapeutic range but below toxic concentrations over a period of timeof about 12 hours or longer.

The term “Cmax” denotes the maximum plasma concentration obtained duringthe dosing interval.

The term “Tmax” denotes the time to maximum plasma concentration (Cmax).

The term T_(1/2) (abs) denotes the amount of time necessary for one-halfof the absorbable dose of opioid to be transferred to plasma.

The term “steady state” means that a plasma concentration for a givendrug has been achieved and which is maintained with subsequent doses ofthe drug at a concentration which is at or above the minimum effectivetherapeutic concentration and is below the minimum toxic plasmaconcentration for a given drug. For opioid analgesics, the minimumeffective therapeutic concentration will be a partially determined bythe amount of pain relief achieved in a given patient. It will be wellunderstood by those skilled in the medical art that pain measurement ishighly subjective and great individual variations may occur amongpatients.

The terms “maintenance therapy” and “chronic therapy” are defined forpurposes of the present invention as the drug therapy administered to apatient after a patient is titrated with an opioid analgesic to a steadystate as defined above.

The term “minimum effective analgesic concentration” or “MEAC” withrespect to concentrations of opioids such as hydrocodone is verydifficult to quantify. However, there is generally a minimally effectiveanalgesic concentration of plasma hydrocodone below which no analgesiais provided. While there is an indirect relationship between, e.g.,plasma hydrocodone levels and analgesia, higher and prolonged plasmalevels are generally associated with superior pain relief. There is alag time or hysteresis, between the time of peak plasmahydrocodone-levels and the time of peak drug effects. This holds truefor the treatment of pain with opioid analgesics in general.

The term “mean resonance time” (MRT) is defined as the average time adrug molecule stays in the body. This calculation, which is a functionof absorption, distribution and elimination, is dependent in part, onthe dosage form containing the active ingredient.

For purposes of the invention, unless further specified, the term “apatient” means that the discussion (or claim) is directed to thepharmacokinetic parameters of an individual patient or subject.

The term “population of patients” means that the discussion (or claim)is directed to the mean pharmacokinetic parameters of at least twopatients or subjects.

The term “breakthrough pain” means pain which the patient experiencesdespite the fact that the patient is being administered generallyeffective amounts of the sustained release solid oral dosage forms ofthe invention containing hydromorphone.

The term “rescue” refers to a dose of an analgesic which is administeredto a patient experiencing breakthrough pain.

The term “effective pain management” means an objective evaluation of ahuman patient's response (pain experienced versus side effects) toanalgesic treatment by a physician as well as subjective evaluation oftherapeutic treatment by the patient undergoing such treatment. Oneskilled in the art will understand that effective analgesia will varyaccording to many factors, including individual patient variability.

The term “immediate release hydrocodone reference formulation” forpurposes of the present invention, is an equivalent amount of thehydrocodone portion of Lortab®, commercially available from UCB Pharma,Inc, or a pharmaceutical product that provides an immediate release ofhydrocodone or a salt thereof.

For purposes of the invention, the controlled release formulationsdisclosed herein and the immediate release control formulations are doseproportional. In such formulations, the pharmacokinetic parameters (e.g.AUC and Cmax) increase linearly from one dosage strength to another.Therefore the pharmacokinetic parameters of a particular dose can beinferred from the parameters of a different dose of the sameformulation.

For purposes of the invention, unless otherwise specified, thepharmacokinetic parameters disclosed herein are based on theadministration of a single dose of a hydrocodone formulation to anindividual patient. Pharmacokinetic parameters based on a patientpopulation will be specified as “mean” data.

The term “first administration” means a single dose of the presentinvention at the initiation of therapy to an individual patient or apatient population.

The controlled-release oral solid dosage forms of the present inventionsurprisingly may be opioid-sparing. It is possible that thecontrolled-release oral solid dosage forms of the present invention maybe dosed at a substantially lower daily dosage in comparison toconventional immediate-release products, with no difference in analgesicefficacy. At comparable daily dosages, greater efficacy may result withthe use of the controlled-release oral solid dosage forms of the presentinvention in comparison to conventional immediate-release products.

BRIEF DESCRIPTION OF THE DRAWINGS

The figures attached herewith are illustrative of embodiments of theinvention and are not meant to limit the scope of the invention asencompassed by the claims.

FIG. 1 is a graphical representation of the mean hydrocodone plasmaconcentration of Example 1, Example 2, Example 3 and an equivalent doseof immediate release hydrocodone.

FIG. 2 is a graphical representation of the mean plasma concentration ofExample 1, Example 2 and Example 3, against different samples ofcontrolled release oxycodone manufactured in accordance with theprocedures of Example 4, and different samples of controlled releasemorphine manufactured in accordance with the procedures of Example 5.

FIG. 3 is a graphical representation of the % fraction hydrocodoneabsorbed over time of Example 1, Example 2, Example 3 and an equivalentdose of immediate release hydrocodone.

DETAILED DESCRIPTION

The above embodiments of the invention can be provided by a wide varietyof controlled release formulations known to those skilled in the art.For example, suitable controlled release dosage forms are disclosed inU.S. Pat. Nos. 4,861,598 and 4,970,075, hereby incorporated by reference

In certain embodiments of the present invention, an effective amount ofopioid in immediate release form is included in the formulation. Theimmediate release form of the opioid is included in an amount which iseffective to shorten the time to maximum concentration of the opioid inthe blood (e.g., plasma), such that the T_(max) is shortened to a timeof e.g., from about 2 to about 5 hours, or from about 2 to about 4hours. It has been discovered that by including such an effective amountof immediate release opioid in the unit dose, the experience ofrelatively higher levels of pain in patients is significantly reduced.In such embodiments, an effective amount of the opioid in immediaterelease form may be coated onto the substrates of the present invention.For example, where the extended release opioid from the formulation isdue to a controlled release coating, the immediate release layer wouldbe overcoated on top of the controlled release coating. On the otherhand, the immediate release layer may be coated onto the surface ofsubstrates wherein the opioid is incorporated in a controlled releasematrix. Where a plurality of the sustained release substrates comprisingan effective unit dose of the opioid (e.g., multiparticulate systemsincluding pellets, spheres, beads and the like) are incorporated into ahard gelatin capsule, the immediate release portion of the opioid dosemay be incorporated into the gelatin capsule via inclusion of thesufficient amount of immediate release opioid as a powder or granulatewithin the capsule. Alternatively, the gelatin capsule itself may becoated with an immediate release layer of the opioid. One skilled in theart would recognize still other alternative manners of incorporating theimmediate release opioid portion into the unit dose. Such alternativesare deemed to be encompassed by the appended claims.

One advantage of the opioid dosage forms of the present invention isthat therapeutic concentrations are generally achieved substantiallywithout significant increases in the intensity and/or degree ofconcurrent side effects, such as nausea, vomiting, or drowsiness, whichare often associated with high blood concentrations of opioids. There isalso evidence to suggest that the use of the present dosage forms leadto a reduced risk of drug addiction.

Active Agent

The controlled release oral dosage forms of the present inventionpreferably include from about 0.5 mg to about 1250 mg hydrocodone or anequivalent amount of a pharmaceutically acceptable salt thereof. In morepreferred embodiments, the dosage form can include from about 5 mg toabout 60 mg, e.g. 15 mg. Suitable pharmaceutically acceptable salts ofhydrocodone include hydrocodone bitartrate, hydrocodone bitartratehydrate, hydrocodone hydrochloride, hydrocodone p-toluenesulfonate,hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodonesulfate, hydrocodone trifluoroacetate, hydrocodone hemipentahydrate,hydrocodone pentafluoropropionate, hydrocodone p-nitrophenylhydrazone,hydrocodone o-methyloxime, hydrocodone semicarbazone, hydrocodonehydrobromide, hydrocodone mucate, hydrocodone oleate, hydrocodonephosphate dibasic, hydrocodone phosphate monobasic, hydrocodoneinorganic salt, hydrocodone organic salt, hydrocodone acetatetrihydrate, hydrocodone bis(heptafuorobutyrate), hydrocodonebis(methylcarbamate), hydrocodone bis(pentafluoropropionate),hydrocodone bis(pyridine carboxylate), hydrocodonebis(trifluoroacetate), hydrocodone chlorhydrate, and hydrocodone sulfatepentahydrate. Preferably, the hydrocodone is present as the bitartratesalt.

The dosage forms of the present invention may further include one ormore additional drugs which may or may not act synergistically with thehydrocodone analgesics of the present invention. Examples of suchadditional drugs include non-steroidal anti-inflammatory agents,including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen,oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Such non-steroidalanti-inflammatory agents also include cyclo-oxygenase inhibitors such ascelecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam,6-methoxy-2 naphthylacetic acid (6-MNA), Vioxx (MK-966), nabumetone(prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, and T-614.as amantadine (1-aminoadamantine), and memantine (3,5dimethylaminoadamantone), their mixtures and pharmaceutically acceptablesalts thereof.

Other additional drugs include nontoxic NMDA receptor antagonists suchdextrorphan, dextromethorphan,3-(1-naphthalennyl)-5-(phosphonomethyl)-L-phenylalanine,3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine,1-(3,5-dimethylphenyl)naphthalene, and 2-(3,5-dimethylphenyl)naphthalene,2SR,4RS-4-(((1H-Tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid;2SR,4RS-4-((((1H-Tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylicacid; E and Z2SR-4-(O-(1H-Tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylicacid; 2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid; 2SR,4RS-4-((1H-Tetrazol-5-yl)thio)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-1H-Tetrazol-1-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(5-mercapto-2H-Tetrazol-2-yl)piperidine-2-carboxylic acid;2SR,4RS-4-(((1H-Tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid;2SR,4RS-4-((5-mercapto-1H-Tetrazol-1-yl)methyl)piperidine-2-carboxylicacid; or 2SR,4RS-4-((5-mercapto-2H-Tetrazol-2-yl)methyl)piperidine-2-carboxylicacid, their mixtures and pharmaceutically acceptable salts thereof.

Other suitable additional drugs which may be included in the dosageforms of the present invention include acetaminophen, aspirin,neuro-active steroids (such as those disclosed in U.S. Ser. No.09/026,520, filed Feb. 20, 1998, hereby incorporated by reference) andother non-opioid analgesics.

For example, if a second (non-opioid) drug is included in theformulation, such drug may be included in controlled release form or inimmediate release form. The additional drug may be incorporated into thecontrolled release matrix along with the opioid; incorporated into thecontrolled release coating; incorporated as a separated controlledrelease layer or immediate release layer; or may be incorporated as apowder, granulation, etc., in a gelatin capsule with the substrates ofthe present invention.

In certain preferred embodiments of the present invention, an effectiveamount of hydrocodone in immediate release form is included in thecontrolled release unit dose hydrocodone formulation to be administered.The immediate release form of the hydrocodone is included in an amountwhich is effective to shorten the time to Cmax of the hydrocodone in theblood (e.g., plasma). In such embodiments, an effective amount of thehydrocodone in immediate release form may be coated onto the substratesof the present invention. For example, where the extended releasehydrocodone from the formulation is due to a controlled release coating,the immediate release layer would be overcoated on top of the controlledrelease coating. On the other hand, the immediate release layer may becoated onto the surface of substrates wherein the hydrocodone isincorporated in a controlled release matrix. Where a plurality of thesustained release substrates comprising an effective unit dose of thehydrocodone (e.g., multiparticulate systems including pellets, spheres,beads and the like) are incorporated into a hard gelatin capsule, theimmediate release portion of the opioid dose may be incorporated intothe gelatin capsule via inclusion of the sufficient amount of immediaterelease hydrocodone as a powder or granulate within the capsule.Alternatively, the gelatin capsule itself may be coated with animmediate release layer of the hydrocodone. One skilled in the art wouldrecognize still other alternative manners of incorporating the immediaterelease hydromorphone portion into the unit dose. Such alternatives aredeemed to be encompassed by the appended claims. It has been discoveredthat by including such an effective amount of immediate releasehydrocodone in the unit dose, the experience of relatively higher levelsof pain in patients is significantly reduced.

Dosage Forms

The controlled-release dosage form may optionally include a controlledrelease material which is incorporated into a matrix along with thehydrocodone, or which is applied as a sustained release coating over asubstrate comprising the drug (the term “substrate” encompassing beads,pellets, spheroids, tablets, tablet cores, etc). The controlled releasematerial may be hydrophobic or hydrophilic as desired. The oral dosageform according to the invention may be provided as, for example,granules, spheroids, pellets (hereinafter collectively referred to as“multiparticulates”). An amount of the multiparticulates which iseffective to provide the desired dose of opioid over time may be placedin a capsule or may be incorporated in any other suitable oral solidform, e.g., compressed into a tablet. On the other hand, the oral dosageform according to the present invention may be prepared as a tablet corecoated with a controlled-release coating, or as a tablet comprising amatrix of drug, controlled release material, and optionally otherpharmaceutically desirable ingredients (e.g., diluents, binders,colorants, lubricants, etc.).

Controlled Release Matrix Formulations

In certain preferred embodiments of the present invention, thecontrolled-release formulation is achieved via a matrix (e.g. a matrixtablet) which includes a controlled-release material as set forth above.A dosage form including a controlled-release matrix provides in-vitrodissolution rates of the opioid within the preferred ranges and thatreleases the opioid in a pH-dependent or pH-independent manner. Thematerials suitable for inclusion in a controlled-release matrix willdepend on the method used to form the matrix. The oral dosage form maycontain between 1% and 80% (by weight) of at least one hydrophilic orhydrophobic controlled release material.

A non-limiting list of suitable controlled-release materials which maybe included in a controlled-release matrix according to the inventioninclude hydrophilic and/or hydrophobic materials, such as gums,cellulose ethers, acrylic resins, protein derived materials, waxes,shellac, and oils such as hydrogenated castor oil, hydrogenatedvegetable oil. However, any pharmaceutically acceptable hydrophobic orhydrophilic controlled-release material which is capable of impartingcontrolled-release of the opioid may be used in accordance with thepresent invention. Preferred controlled-release polymers includealkylcelluloses such as ethylcellulose, acrylic and methacrylic acidpolymers and copolymers, and cellulose ethers, especiallyhydroxyalkylcelluloses (especially hydroxypropylmethylcellulose) andcarboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymersand copolymers include methyl methacrylate, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylicacid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.Certain preferred embodiments utilize mixtures of any of the foregoingcontrolled-release materials in the matrices of the invention.

The matrix also may include a binder. In such embodiments, the binderpreferably contributes to the controlled-release of the hydrocodone fromthe controlled-release matrix.

Preferred hydrophobic binder materials are water-insoluble with more orless pronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic binder materials useful in the invention have a meltingpoint from about 30 to about 200° C., preferably from about 45 to about90° C. When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° and 90° C. Of the longchain (C₈-C₅₀) hydrocarbon materials, fatty (aliphatic) alcohols arepreferred. The oral dosage form may contain up to 80% (by weight) of atleast one digestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 80% (by weight) of atleast one polyalkylene glycol. Specifically, the hydrophobic bindermaterial may comprise natural or synthetic waxes, fatty alcohols (suchas lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol),fatty acids, including but not limited to fatty acid esters, fatty acidglycerides (mono-, di-, and tri-glycerides), hydrogenated fats,hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobicand hydrophilic materials having hydrocarbon backbones. Suitable waxesinclude, for example, beeswax, glycowax, castor wax and carnauba wax.For purposes of the present invention, a wax-like substance is definedas any material which is normally solid at room temperature and has amelting point of from about 30 to about 100° C.

Preferred hydrophobic binder materials which may be used in accordancewith the present invention include digestible, long chain (C₈-C₅₀,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils, natural and synthetic waxes and polyalkylene glycols.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of the long-chain hydrocarbon binder materials, fatty(aliphatic) alcohols are preferred in certain embodiments. The oraldosage form may contain up to 80% (by weight) of at least onedigestible, long chain hydrocarbon.

In certain preferred embodiments, a combination of two or morehydrophobic binder materials are included in the matrix formulations. Ifan additional hydrophobic binder material is included, it is preferablyselected from natural and synthetic waxes, fatty acids, fatty alcohols,and mixtures of the same. Examples include beeswax, carnauba wax,stearic acid and stearyl alcohol. This list is not meant to beexclusive.

One particular suitable controlled-release matrix comprises at least onewater soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofopioid release required. The aliphatic alcohol may be, for example,lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularlypreferred embodiments of the present oral dosage form, however, the atleast one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. Theamount of the aliphatic alcohol in the present oral dosage form will bedetermined, as above, by the precise rate of opioid release required. Itwill also depend on whether at least one polyalkylene glycol is presentin or absent from the oral dosage form. In the absence of at least onepolyalkylene glycol, the oral dosage form preferably contains between20% and 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycolis present in the oral dosage form, then the combined weight of thealiphatic alcohol and the polyalkylene glycol preferably constitutesbetween 20% and 50% (by wt) of the total dosage.

In one preferred embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of thehydroxyalkyl cellulose to the aliphatic alcohol/polyalkylene glycol ofbetween 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4being particularly preferred.

The polyalkylene glycol may be, for example, polypropylene glycol or,which is preferred, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferred between1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled-release matrix comprises an alkylcellulose(especially ethylcellulose), a C₁₂ to C₃₆ aliphatic alcohol and,optionally, a polyalkylene glycol.

In addition to the above ingredients, a controlled-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

In order to facilitate the preparation of a solid, controlled-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, controlled-release oral dosage form according to the presentinvention comprising incorporating opioids or a salt thereof in acontrolled-release matrix. Incorporation in the matrix may be effected,for example, by

(a) forming granules comprising at least one hydrophobic and/orhydrophilic material as set forth above (e.g., a water solublehydroxyalkyl cellulose) together with the hydrocodone;

(b) mixing the at least one hydrophobic and/or hydrophilicmaterial-containing granules with at least one C₁₂-C₃₆ aliphaticalcohol, and

(c) optionally, compressing and shaping the granules.

The granules may be formed by any of the procedures well-known to thoseskilled in the art of pharmaceutical formulation. For example, in onepreferred method, the granules may be formed by wet granulatinghydroxyalkyl cellulose/opioid with water. In a particularly preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the opioid.

The matrices of the present invention may also be prepared via a meltpellitization technique. In such circumstance, the opioid in finelydivided form is combined with a binder (also in particulate form) andother optional inert ingredients, and thereafter the mixture ispelletized, e.g., by mechanically working the mixture in a high shearmixer to form the pellets (granules, spheres). Thereafter, the pellets(granules, spheres) may be sieved in order to obtain pellets of therequisite size. The binder material is preferably in particulate formand has a melting point above about 40° C. Suitable binder substancesinclude, for example, hydrogenated castor oil, hydrogenated vegetableoil, other hydrogenated fats, fatty alcohols, fatty acid esters, fattyacid glycerides, and the like.

Controlled-release matrices can also be prepared by, e.g.,melt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicbinder material, e.g. a wax, and incorporating a powdered drug therein.To obtain a controlled release dosage form, it may be necessary toincorporate a hydrophobic controlled release material, e.g.ethylcellulose or a water-insoluble acrylic polymer, into the molten waxhydrophobic binder material. Examples of controlled-release formulationsprepared via melt-granulation techniques are found, e.g., in U.S. Pat.No. 4,861,598, assigned to the Assignee of the present invention andhereby incorporated by reference in its entirety.

The additional hydrophobic binder material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve controlled release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like binder substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a controlled release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired. The quantities ofthese additional materials will be sufficient to provide the desiredeffect to the desired formulation.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theopioid analgesic, together with a controlled release material andpreferably a binder material to obtain a homogeneous mixture. Thehomogeneous mixture is then heated to a temperature sufficient to atleast soften the mixture sufficiently to extrude the same. The resultinghomogeneous mixture is then extruded, e.g., using a twin-screw extruder,to form strands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides controlled release of the therapeuticallyactive agent for a time period of from about 8 to about 24 hours.

An optional process for preparing the melt extrusioned formulations ofthe present invention includes directly metering into an extruder ahydrophobic controlled release material, a therapeutically active agent,and an optional binder material; heating the homogenous mixture;extruding the homogenous mixture to thereby form strands; cooling thestrands containing the homogeneous mixture; cutting the strands intoparticles having a size from about 0.1 mm to about 12 mm; and dividingsaid particles into unit doses. In this aspect of the invention, arelatively continuous manufacturing procedure is realized.

Plasticizers, such as those described hereinabove, may be included inmelt-extruded matrices. The plasticizer is preferably included as fromabout 0.1 to about 30% by weight of the matrix. Other pharmaceuticalexcipients, e.g., talc, mono or poly saccharides, colorants, flavorants,lubricants and the like may be included in the controlled releasematrices of the present invention as desired. The amounts included willdepend upon the desired characteristic to be achieved.

The diameter of the extruder aperture or exit port can be adjusted tovary the thickness of the extruded strands. Furthermore, the exit partof the extruder need not be round; it can be oblong, rectangular, etc.The exiting strands can be reduced to particles using a hot wire cutter,guillotine, etc. A melt extruded multiparticulate system can be, forexample, in the form of granules, spheroids or pellets depending uponthe extruder exit orifice. For purposes of the present invention, theterms “melt-extruded multiparticulate(s)” and “melt-extrudedmultiparticulate system(s)” and “melt-extruded particles” shall refer toa plurality of units, preferably within a range of similar size and/orshape and containing one or more active agents and one or moreexcipients, preferably including a hydrophobic controlled releasematerial as described herein. Preferably the melt-extrudedmultiparticulates will be of a range of from about 0.1 to about 12 mm inlength and have a diameter of from about 0.1 to about 5 mm. In addition,it is to be understood that the melt-extruded multiparticulates can beany geometrical shape within this size range, such as, simply by way ofexample, beads, seeds, pellets, etc. Alternatively, the extrudate maysimply be cut into desired lengths and divided into unit doses of thetherapeutically active agent without the need of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared that includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective controlled release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),described in additional detail above and hereby incorporated byreference.

Optionally, the controlled-release matrix multiparticulate systems ortablets can be coated, or the gelatin capsule can be further coated,with a controlled release coating such as the controlled releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic and/or hydrophilic controlled-release material toobtain a weight gain level from about 2 to about 25 percent, althoughthe overcoat may be greater depending upon, e.g., the physicalproperties of the particular opioid analgesic used and the desiredrelease rate, among other things.

The dosage forms of the present invention may further includecombinations of melt-extruded multiparticulates containing one or moreopioid analgesics. Furthermore, the dosage forms can also include anamount of an immediate release therapeutically active agent for prompttherapeutic effect. The immediate release therapeutically active agentmay be incorporated, e.g., as separate pellets within a gelatin capsule,or may be coated on the surface of, e.g., beads or melt extrudedmultiparticulates. The unit dosage forms of the present invention mayalso contain a combination of, e.g., controlled release beads and matrixmultiparticulates to achieve a desired effect.

The controlled-release formulations of the present invention preferablyslowly release the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofcontrolled-release material, by varying the amount of plasticizerrelative to other matrix constituents, hydrophobic material, by theinclusion of additional ingredients or excipients, by altering themethod of manufacture, etc.

In other embodiments of the invention, melt-extruded formulations areprepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

Typical melt-extrusion production systems suitable for use in accordancewith the present invention include a suitable extruder drive motorhaving variable speed and constant torque control, start-stop controls,and ammeter. In addition, the production system will include atemperature control console which includes temperature sensors, coolingmeans and temperature indicators throughout the length of the extruder.In addition, the production system will include an extruder such astwin-screw extruder which consists of two counter-rotating intermeshingscrews enclosed within a cylinder or barrel having an aperture or die atthe exit thereof. The feed materials enter through a feed hopper and aremoved through the barrel by the screws and are forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into themultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C.W. Brabender Instruments, Inc.of South Hackensack, N.J. Other suitable apparatus will be apparent tothose of ordinary skill in the art.

A further aspect of the invention is related to the preparation ofmelt-extruded multiparticulates as set forth above in a manner whichcontrols the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, it has beensurprisingly found that the release rate of the therapeutically activeagent from the, e.g., multiparticulate extrudate, can be alteredsignificantly. In certain embodiments, it has been surprisingly foundthat the pH dependency of the extruded product can be altered as well.

Thus, in a further aspect of the invention, the melt-extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. It has beensurprisingly found that extruded multiparticulates prepared according tothe invention using the Leistritz extruder under vacuum provides amelt-extruded product having different physical characteristics. Inparticular, the extrudate is substantially non-porous when magnified,e.g., using a scanning electron microscope which provides an SEM(scanning electron micrograph). Contrary to conventional thought, it hasbeen found that such substantially non-porous formulations provide afaster release of the therapeutically active agent, relative to the sameformulation prepared without vacuum. SEMs of the multiparticulatesprepared using an extruder under vacuum appear very smooth, and themultiparticulates tend to be more robust than those multiparticulatesprepared without vacuum. It has been observed that in at least certainformulations, the use of extrusion under vacuum provides an extrudedmultiparticulate product which is more pH-dependent than its counterpartformulation prepared without vacuum.

Processes for Preparing Matrix Beads

Controlled-release dosage forms according to the present invention mayalso be prepared as matrix beads formulations. The matrix beads includea spheronising agent and the hydrocodone.

The hydrocodone preferably comprises from about 0.01 to about 99% byweight of the matrix bead by weight. It is preferable that thehydrocodone is included as about 0.1 to about 50% by weight of thematrix bead.

Spheronising agents which may be used to prepare the matrix beadformulations of the present invention include any art-known spheronisingagent. Cellulose derivatives are preferred, and microcrystallinecellulose is especially preferred. A suitable microcrystalline celluloseis, for example, the material sold as Avicel PH 101 (Trade Mark, FMCCorporation). The spheronising agent is preferably included as about 1to about 99% of the matrix bead by weight.

In addition to the active ingredient and spheronizing agent, thespheroids may also contain a binder. Suitable binders, such as lowviscosity, water soluble polymers, will be well known to those skilledin the pharmaceutical art. However, water soluble hydroxy loweralkylcellulose, such as hydroxypropylcellulose, are preferred.

In addition to the opioid analgesic and spheronising agent, the matrixbead formulations of the present invention may include a controlledrelease material such as those described hereinabove. Preferredcontrolled-release materials for inclusion in the matrix beadformulations include acrylic and methacrylic acid polymers orcopolymers, and ethylcellulose. When present in the formulation, thecontrolled-release material will be included in amounts of from about 1to about 80% of the matrix bead, by weight. The controlled-releasematerial is preferably included in the matrix bead formulation in anamount effective to provide controlled release of the opioid analgesicfrom the bead.

Pharmaceutical processing aids such as binders, diluents, and the likemay be included in the matrix bead formulations. Amounts of these agentsincluded in the formulations will vary with the desired effect to beexhibited by the formulation.

The matrix beads may be overcoated with a controlled-release coatingincluding a controlled-release material such as those describedhereinabove. The controlled-release coating is applied to a weight gainof from about 5 to about 30%. The amount of the controlled-releasecoating to be applied will vary according to a variety of factors, e.g.,the composition of the matrix bead and the chemical and/or physicalproperties of the opioid analgesic (i.e., hydrocodone).

Matrix beads are generally prepared by granulating the spheronisingagent together with the opioid analgesic, e.g. by wet granulation. Thegranulate is then spheronized to produce the matrix beads. The matrixbeads are then optionally overcoated with the controlled release coatingby methods such as those described hereinabove.

Another method for preparing matrix beads, for example, by (a) forminggranules comprising at least one water soluble hydroxyalkyl celluloseand opioid or an opioid salt; (b) mixing the hydroxyalkyl cellulosecontaining granules with at least one C₁₂-C₃₆ aliphatic alcohol; and (c)optionally, compressing and shaping the granules. Preferably, thegranules are formed by wet granulating the hydroxyalkyl cellulose/opioidwith water. In a particularly preferred embodiment of this process, theamount of water added during the wet granulation step is preferablybetween 1.5 and 5 times, especially between 1.75 and 3.5 times, the dryweight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such as hydroxy propylcellulose, are preferred. Additionally (or alternatively) the spheroidsmay contain a water insoluble polymer, especially an acrylic polymer, anacrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer,or ethyl cellulose. In such embodiments, the sustained-release coatingwill generally include a water insoluble material such as (a) a wax,either alone or in admixture with a fatty alcohol; or (b) shellac orzein.

Controlled Release Bead Formulations

In one especially preferred embodiment, the oral dosage form comprisesan effective number of controlled release spheroids contained within agelatin capsule.

In another preferred embodiment of the present invention, thecontrolled-release dosage form comprises spheroids containing the activeingredient coated with a controlled-release coating including acontrolled release material. The term spheroid is known in thepharmaceutical art and means, e.g., a spherical granule having adiameter of between 0.1 mm and 2.5 mm, especially between 0.5 mm and 2mm.

The spheroids are preferably film coated with a controlled releasematerial that permits release of the opioid (or salt) at a controlledrate in an aqueous medium. The film coat is chosen so as to achieve, incombination with the other stated properties, the in-vitro release rateoutlined above (e.g., at least about 12.5% released after 1 hour). Thecontrolled-release coating formulations of the present inventionpreferably produce a strong, continuous film that is smooth and elegant,capable of supporting pigments and other coating additives, non-toxic,inert, and tack-free.

Coatings

The dosage forms of the present invention may optionally be coated withone or more coatings suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. When a pH-independent coating isdesired, the coating is designed to achieve optimal release regardlessof pH-changes in the environmental fluid, e.g., the GI tract. Otherpreferred embodiments include a pH-dependent coating that releases theopioid in desired areas of the gastro-intestinal (GI) tract, e.g., thestomach or small intestine, such that an absorption profile is providedwhich is capable of providing at least about twelve hour and preferablyup to twenty-four hour analgesia to a patient. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

Formulations according to the invention that utilize pH-dependentcoatings may also impart a repeat-action effect whereby unprotected drugis coated over an enteric coat and is released in the stomach, while theremainder, being protected by the enteric coating, is released furtherdown the gastrointestinal tract. Coatings which are pH-dependent may beused in accordance with the present invention include a controlledrelease material such as, e.g., shellac, cellulose acetate phthalate(CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulosephthalate, and methacrylic acid ester copolymers, zein, and the like.

In another preferred embodiment, the present invention is related to astabilized solid controlled dosage form comprising an opioid coated witha hydrophobic controlled release material selected from (i) analkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. Thecoating may be applied in the form of an organic or aqueous solution ordispersion.

In certain preferred embodiments, the controlled release coating isderived from an aqueous dispersion of the hydrophobic controlled releasematerial. The coated substrate containing the opioid(s) (e.g., a tabletcore or inert pharmaceutical beads or spheroids) is then cured until anendpoint is reached at which the substrate provides a stabledissolution. The curing endpoint may be determined by comparing thedissolution profile (curve) of the dosage form immediately after curingto the dissolution profile (curve) of the dosage form after exposure toaccelerated storage conditions of, e.g., at least one month at atemperature of 40° C. and a relative humidity of 75%. These formulationsare described in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493,assigned to the Assignee of the present invention and herebyincorporated by reference. Other examples of controlled-releaseformulations and coatings which may be used in accordance with thepresent invention include Assignee's U.S. Pat. Nos. 5,324,351;5,356,467, and 5,472,712, hereby incorporated by reference in theirentirety.

In preferred embodiments, the controlled release coatings include aplasticizer such as those described herein below.

In certain embodiments, it is necessary to overcoat the substratecomprising the opioid analgesic with a sufficient amount of the aqueousdispersion of e.g., alkylcellulose or acrylic polymer, to obtain aweight gain level from about 2 to about 50%, e.g., about 2 to about 25%in order to obtain a controlled-release formulation. The overcoat may belesser or greater depending upon the physical properties of thetherapeutically active agent and the desired release rate, the inclusionof plasticizer in the aqueous dispersion and the manner of incorporationof the same, for example.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses arecontrolled release materials well suited for coating the substrates,e.g., beads, tablets, etc. according to the invention. Simply by way ofexample, one preferred alkylcellulosic polymer is ethylcellulose,although the artisan will appreciate that other cellulose and/oralkylcellulose polymers may be readily employed, singly or on anycombination, as all or part of a hydrophobic coatings according to theinvention.

One commercially—available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the controlledrelease material comprising the controlled-release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonia methacrylate copolymers. Ammonia methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonia methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Rohm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit RL andEudragit RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain acontrolled-release formulation having a desirable dissolution profile.Desirable controlled-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic controlled release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the controlled-release coating. For example, becauseethylcellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining controlled-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tibutyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talc tothe controlled release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

Preparation of Coated Bead Formulations

When an aqueous dispersion of hydrophobic material is used to coatsubstrates, e.g., inert pharmaceutical beads such as no pariel 18/20beads, a plurality of the resultant stabilized solid controlled-releasebeads may thereafter be placed in a gelatin capsule in an amountsufficient to provide an effective controlled-release dose when ingestedand contacted by an environmental fluid, e.g., gastric fluid ordissolution media.

The stabilized controlled-release bead formulations of the presentinvention slowly release the opioid analgesic, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the formulations of the invention can bealtered, for example, by varying the amount of overcoating with theaqueous dispersion of hydrophobic controlled release material, alteringthe manner in which the plasticizer is added to the aqueous dispersionof hydrophobic controlled release material, by varying the amount ofplasticizer relative to hydrophobic controlled release material, by theinclusion of additional ingredients or excipients, by altering themethod of manufacture, etc. The dissolution profile of the ultimateproduct may also be modified, for example, by increasing or decreasingthe thickness of the controlled release coating.

Substrates coated with a therapeutically active agent are prepared, e.g.by dissolving the therapeutically active agent in water and thenspraying the solution onto a substrate, for example, no pariel 18/20beads, using a Wuster insert. Optionally, additional ingredients arealso added prior to coating the beads in order to assist the binding ofthe opioid to the beads, and/or to color the solution, etc. For example,a product which includes hydroxypropyl methylcellulose, etc. with orwithout colorant (e.g., Opadry®, commercially available from Colorcon,Inc.) may be added to the solution and the solution mixed (e.g., forabout 1 hour) prior to application of the same onto the substrate. Theresultant coated substrate may then be optionally overcoated with abarrier agent, to separate the therapeutically active agent from thehydrophobic controlled-release coating.

An example of a suitable barrier agent is one which compriseshydroxypropyl methylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The substrates may then be overcoated with an aqueous dispersion of thehydrophobic controlled release material. The aqueous dispersion ofhydrophobic controlled release material preferably further includes aneffective amount of plasticizer, e.g. triethyl citrate. Pre-formulatedaqueous dispersions of ethylcellulose, such as Aquacoat® or Surelease®,may be used. If Surelease® is used, it is not necessary to separatelyadd a plasticizer. Alternatively, pre-formulated aqueous dispersions ofacrylic polymers such as Eudragit® can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color can be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

The plasticized aqueous dispersion of hydrophobic controlled releasematerial may be applied onto the substrate comprising thetherapeutically active agent by spraying using any suitable sprayequipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while theacrylic polymer coating is sprayed on. A sufficient amount of theaqueous dispersion of hydrophobic material to obtain a predeterminedcontrolled-release of said therapeutically active agent when said coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, ispreferably applied, taking into account the physical characteristics ofthe therapeutically active agent, the manner of incorporation of theplasticizer, etc. After coating with the hydrophobic controlled releasematerial, a further overcoat of a film-former, such as Opadry®, isoptionally applied to the beads. This overcoat is provided, if at all,in order to substantially reduce agglomeration of the beads.

The release of the therapeutically active agent from thecontrolled-release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic controlled releasematerial to water soluble material is determined by, among otherfactors, the release rate required and the solubility characteristics ofthe materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The controlled-release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

The controlled-release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The controlled-release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864, all of which are hereby incorporated by reference. Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

Another method of producing controlled release bead formulationssuitable for about 24-hour administration is via powder layering. U.S.Pat. No. 5,411,745, assigned to the Assignee of the present inventionand hereby incorporated by reference in its entirety, teachespreparation of 24-hour morphine formulations prepared via powderlayering techniques utilizing a processing aid consisting essentially ofhydrous lactose impalpable. The powder-layered beads are prepared byspraying an aqueous binder solution onto inert beads to provide a tackysurface, and subsequently spraying a powder that is a homogenous mixtureof morphine sulfate and hydrous lactose impalpable onto the tacky beads.The beads are then dried and coated with a hydrophobic material such asthose described hereinabove to obtain the desired release of drug whenthe final formulation is exposed to environmental fluids. An appropriateamount of the controlled release beads are then, e.g. encapsulated toprovide a final dosage form which provides effective plasmaconcentrations of morphine for about 12 hours.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not meant to be construed to limit the claims in anymanner whatsoever.

Example 1

Hydrocodone sustained release tablets were produced with the formula setforth in Table 1 below:

TABLE 1 Ingredients Amt/Unit (mg) Amount/Batch (gm) HydrocodoneBitartrate 15.0 150.0 Spray Dried Lactose 56.0 560.0 Povidone 4.0 40.0Eudragit RS30D (solids) 10.0 100.0 Triacetin 2.0 20.0 Stearyl Alcohol20.0 200.0 Talc 2.0 20.0 Magnesium Stearate 1.0 10.0 Total 110.0 1100.0

According to the following procedure:

-   1. Retardant dispersion: Blend Eudragit RS30D and Triacetin using a    lightnin mixer.-   2. Melt Stearyl Alcohol.-   3. Spray retardant dispersion onto Hydrocodone Bitartrate, Spray    Dried Lactose, and Povidone using a fluid bed granulator.-   4. Dry batch on a stainless steel tray for 15 minutes, or till    constant weight.-   5. Incorporate the melted Stearyl Alcohol into the batch using a    Hobart mixer.-   6. Dry waxed granulation on a stainless steel tray for 30 minutes,    or temperature of granulation reaches 35° C. or less.-   7. Mill the cooled granulation through a CoMil.-   8. Lubricate the granulation with talc and magnesium stearate using    a Hobart Mixer.-   9. Compress the granulation into tablets using a tablet press.

The tablets were then tested for dissolution using the followingprocedure:

-   1. Apparatus: USP Method 1 (basket), 100 rpm.-   2. Medium: 700 ml SGF for 55 min, thereafter 900 ml of SIF without    enzyme-   3. Sampling time: 1, 2, 4, 8 and 12 hours.-   4. Analytical: High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table II below:

TABLE II Time (Hours) % Dissolved 1 39.7 2 51.5 4 67.4 8 86.4 12 96.1

The Cmax and Tmax were then obtained for Example 1 and an immediaterelease reference standard in a bioavailability study comparinghydrocodone 15 mg administered as an immediate release formulation(Lortab 7.5 mg×2) to the above CR formulation in healthy human subjects,as set forth in Table III below:

TABLE III Pharmacokinetic data Hydrocodone Bitartrate Cmax (ng/ml) 35.4IR reference product Cmax (ng/ml) 13.4 CR product Cmax (CR)/Cmax (IR)38% Tmax (hr) 1.32 IR reference product Tmax (hr) 4.07 CR product

Example 2

Hydrocodone sustained release tablets were produced with the formula setforth in Table IV below:

TABLE IV Ingredients Amt/Unit (mg) Amt/Batch (g) Hydrocodone Bitartrate15.0 150.0 Spray Dried Lactose 51.0 510.0 Povidone 4.0 40.0 EudragitRS30D 10.0 100.0 (solids) Triacetin 2.0 20.0 Stearyl Alcohol 25.0 250.0Talc 2.0 20.0 Magnesium Stearate 1.0 10.0 Total 110.0 1100.0

according to the procedure of Example 1,

The dissolution parameters were then obtained using the procedure ofExample 1. The results are set forth in table V below:

TABLE V Time (Hours) % Dissolved 1 36 2 45.8 4 60.5 8 78.9 12 90.4

Example 3

Hydrocodone sustained release capsules were produced with the formulaset forth in Table VI below:

TABLE VI Ingredients Amt/Unit (mg) Amt/Batch (g) Hydrocodone Bitartrate15.0 320.0 Eudragit RSPO 76.0 1520.0 Eudragit RLPO 4.0 80.0 StearylAlcohol 25.0 500.0 Total 120.0 2400.0

According to the following procedure:

-   1. Blend milled Stearyl Alcohol, Eudragit RLPO, Hydrocodone    Bitartrate, and Eudragit RSPO using a Hobart Mixer.-   2. Extrude the granulation using a Powder Feeder, Melt Extruder    (equipped with the 6×1 mm die head), Conveyor, Lasermike, and    Pelletizer under the following conditions:

Zone 1  10° C. Zone 2  20° C. Zone 3 120° C. Zone 4 120° C. Zone 5 120°C. Zone 6 120° C. Zone 7  95° C. Zone 8  95° C. MGA 120° C. Die 117° C.

-   Powder feed rate-40 g/min; screw speed-185 rpm; vacuum˜980 mBar-   Conveyor-such that diameter of extrudate is 1 mm-   Pelletizer-such that pellets are cut to 1 mm in length-   3. Screen pellets using #16 mesh and #20 mesh screens. Collect    material that passes through the #16 mesh screen and is retained on    the #20 mesh screen.-   4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT    114 mg and NMT 126 mg.

The dissolution parameters were then obtained using the procedure ofExample 1. The results are set forth in table VII below:

TABLE VII Time (Hours) % Dissolved 1 23.9 2 34.7 4 51.7 8 74.6 12 85.2

Example 4

Oxycodone sustained release tablets were produced with the formula setforth in Table VIII below:

TABLE VIII Ingredients Amt/Unit (mg) Amount/Batch (gm) Oxycodone HCl20.0 22.0 Spray Dried Lactose 59.25 65.175 Povidone 5.0 5.5 EudragitRS30D (solids) 10.0 11.0 Triacetin 2.0 2.2 Stearyl Alcohol 25.0 27.5Talc 2.5 2.75 Magnesium Stearate 1.25 1.375 Opadry Pink Y-S-14518A 4.04.26 Total 129.0 141.76

According to the following procedure:

-   1. Granulation: Spray the Eudragit/Triacetin dispersion onto the    Oxycodone HCl, Spray Dried Lactose and Povidone using a fluid bed    granulator.-   2. Milling: Discharge the granulation and pass through a mill.-   3. Waxing: Melt the stearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   4. Milling: Pass the cooled granulation through a mill,-   5. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   6. Compression: Compress the granulation into tablets using a tablet    press.-   7. Film coating: Apply an aqueous film coat to the tablets.

The tablets were then tested for dissolution using the followingprocedure:

-   1. Apparatus: USP Type II (paddle), 150 rpm.-   2. Medium: 700 ml SGF for first hour, thereafter made 900 ml with    phosphate buffer to pH 7.5.-   3. Sampling time: 1, 2, 4, 8, 12, 18 and 24 hours.-   4. Analytical: High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table IX below:

TABLE IX Time (hrs) % Dissolved 1 45 2 55 4 70 8 87 12 96 18 101 24 102

The Cmax and Tmax were then obtained for Example 4 and an immediaterelease reference standard in a bioavailability study, as set forth inTable X below:

TABLE X Pharmacokinetic data Oxycodone HCl Cmax (ng/ml) IR referenceproduct 38.2 Cmax (ng/ml) CR product 21.7 Cmax (CR)/Cmax (IR) 57% Tmax(hr) IR reference product 1.10 Tmax (hr) CR product 2.62

Example 5

Morphine sustained release tablets were produced with the formula setforth in Table XI below:

TABLE XI Ingredients Amount/unit (mg) Amount/batch (kg) Morphine sulfate30.0 138.0 Spray Dried Lactose 70.0 322.0 Hydroxyethyl cellulose 10.046.0 Cetostearyl alcohol 35.0 161.0 Talc 3.0 13.8 Magnesium stearate 2.09.2 Opadry YS-1-4729 5.0 23.0 Total 155.0 713.0

According to the following procedure:

-   1. Granulation: Add water to the Morphine sulfate, Spray Dried    Lactose and Hydroxyethyl cellulose in a mixer and dry using a fluid    bed granulator.-   2. Screening: Discharge the granulation and pass through a sieve.-   3. Waxing: Melt the cetostearyl alcohol and add to the milled    granulation using a mixer. Allow to cool.-   4. Screening: Pass the cooled granulation through a sieve.-   5. Lubrication: Lubricate the granulation with talc and magnesium    stearate using a mixer.-   6. Compression: Compress the granulation into tablets using a tablet    press.-   7. Film coating: Apply an aqueous film coat to the tablets.

The tablets were then tested for dissolution using the followingprocedure:

-   1. Apparatus: USP Method I (Basket), 50 rpm-   2. Medium: 900 ml of Purified Water, 37° C.-   3. Sampling time: 1, 2, 3, 4, and 6 hours.-   4. Analytical: UV detection, 285 nm and 305 nm, 2-point method using    5-cm cell.

The dissolution parameters are set forth in Table XII below:

TABLE XII Time (Hours) % Dissolved 1 34.2 2 49.9 3 64.2 4 75.5 6 90.3

The Cmax and Tmax were then obtained for Example 5 and an immediaterelease reference standard in a bioavailability study, as set forth inTable XIII below:

TABLE XIII Pharmacokinetic data Morphine Sulphate Cmax (ng/ml) IRreference product 22.1 Cmax (ng/ml) CR product 12 Cmax (CR)/Cmax (IR)54% Tmax (hr) IR reference product 0.98 Tmax (hr) CR product 2.09

Example 6

The pharmacokinetic parameters of Example 1, Example 4 and Example 5were compared to each other. It was surprisingly found that even thoughthe dissolution of the hydrocodone HCl controlled release tablets ofexample 1 were very similar to the dissolution of the controlled releaseoxycodone tablets of example 4 and the morphine sulfate controlledrelease tablets of example 5, the Cmax ratio of CR to IR for thehydrocodone formulation is 38%, whereas the oxycodone tablets andmorphine tablets are over 50%. The comparative results are set forth inTable XIV below:

TABLE XIV Hydrocodone Oxycodone Morphine Pharmacokinetic data BitartrateHCl Sulphate Cmax (ng/ml) 35.4 38.2 22.1 IR reference product Cmax(ng/ml) 13.4 21.7 12 CR product Cmax (CR)/Cmax (IR) 38% 57% 54% Tmax(hr) 1.32 1.10 0.98 IR reference product Tmax (hr) 4.07 2.62 2.09 CRproduct

Example 7

A single dose, four treatment, open label, pharmacokinetic comparison ofcontrolled release hydrocodone formulations of Example 1, Example 2,Example 3 and two immediate release hydrocodone bitartrate 7.5mg/Acetaminophen 500 mg tablets (IR Example) in fasted normal volunteerswas conducted. The plasma concentrations for these formulations are setforth in tables 15-18 below:

TABLE 15 Hydrocodone Plasma Concentration (ng/mL) after administrationof one (1) Controlled-Release Hydrocodone Bitartrate 15 mgtablet-Formulation A Time (hours) Subject −0.08 0.5 0.75 1 2 3 4 6 9 1218 24 30 36 1 0.00 4.55 11.1 9.11 15.8 15.5 17.4 15.4 14.5 12.1 6.333.58 2.25 1.29 2 0.00 7.81 8.76 9.20 11.3 14.8 15.5 14.5 10.5 9.30 5.403.39 2.10 0.921 3 0.00 4.63 7.66 8.95 15.9 15.6 16.9 16.3 12.3 9.41 6.554.10 2.38 0.986 4 0.00 3.48 9.48 9.11 10.7 11.9 13.0 12.4 10.7 8.96 5.223.08 1.56 0.558 5 0.00 1.43 4.25 7.20 12.8 13.5 13.0 12.5 9.62 7.01 4.383.26 1.93 1.01 6 0.00 4.69 7.60 10.5 12.8 13.9 13.3 15.1 12.3 8.59 4.523.11 1.59 0.702 7 0.00 0.56 1.86 3.85 7.54 8.26 8.18 8.90 6.23 4.56 2.991.61 0.752 0.00 8 0.00 3.68 7.61 11.5 12.4 13.2 12.7 12.5 9.10 7.09 4.332.93 1.24 0.509 9 0.00 8.06 9.79 9.98 11.4 10.7 11.4 11.9 7.66 5.98 3.852.10 1.12 0.573 10  0.00 3.83 5.71 7.84 8.49 10.8 11.6 11.5 8.02 6.703.34 2.33 1.31 0.00 11  0.00 3.64 5.20 8.00 10.3 11.8 12.5 10.8 7.447.84 4.75 2.21 1.11 0.00 12  0.00 3.07 6.14 8.51 14.3 15.0 14.9 14.712.1 7.75 4.34 2.52 1.69 0.859 13  0.00 1.95 3.82 4.47 9.55 9.15 8.318.05 5.85 3.93 2.45 7.68 1.35 1.07 14  0.00 2.21 4.56 7.33 11.2 12.913.3 13.2 10.6 8.41 4.68 3.11 2.35 0.978 MEAN 0.00 3.83 6.68 8.25 11.712.6 13.0 12.7 9.78 7.69 4.51 3.22 1.62 0.675 SD 0.00 2.13 2.62 2.102.48 2.31 2.70 2.41 2.54 2.09 1.15 1.44 0.513 0.425 % CV 0.00 21.7 39.225.5 21.2 18.3 20.8 19.0 26.0 27.2 25.5 44.7 31.7 63.0

TABLE 16 Hydrocodone Plasma Concentration (ng/mL) after administrationof one (1) Controlled-Release Hydrocodone Bitartrate 15 mgtablet-Formulation B Time (hours) Subject −0.08 0.5 0.75 1 2 3 4 6 9 1218 24 30 36 1 0.00 3.18 5.64 11.8 11.4 12.4 13.5 14.3 11.4 9.28 5.693.23 2.23 1.10 2 0.00 2.61 7.04 8.53 10.7 12.4 11.5 13.6 11.4 9.25 6.434.13 2.59 1.35 3 0.00 5.49 7.57 9.67 13.5 15.6 15.7 14.4 12.6 9.41 7.835.19 3.45 1.77 4 0.00 2.71 5.67 6.35 8.88 11.3 13.7 12.0 8.72 8.18 5.584.33 2.63 1.26 5 0.00 3.98 6.59 7.38 10.6 11.8 11.6 9.42 6.75 4.81 5.283.67 2.43 1.25 6 0.00 0.711 2.85 7.98 12.9 13.6 13 13.8 10.1 8.04 5.173.71 2.33 0.940 7 0.00 1.82 3.03 3.97 7.22 8.04 8.05 7.87 5.97 3.77 2.532.12 1.94 1.19 8 0.00 2.47 3.99 6.03 10.9 13.2 13.8 12.6 9.49 7.60 6.114.74 2.38 0.856 9 0.00 5.02 10.4 8.48 9.06 9.90 9.88 7.96 4.78 3.99 3.773.42 1.53 0.805 10  0.00 3.20 8.17 10.7 9.08 10.7 11.8 11.2 9.08 6.203.38 2.75 1.84 0.672 11  0.00 4.20 6.86 6.36 9.97 11.3 11.3 10.2 7.795.08 4.38 2.67 1.53 0.815 12  0.00 4.73 7.71 9.48 11.9 15.1 16.5 15.513.2 8.89 4.58 3.60 2.67 2.12 13  0.00 1.56 2.87 3.89 6.31 7.43 7.877.64 7.01 5.34 3.57 2.12 1.35 1.41 14  0.00 0.663 2.20 3.86 8.74 14.715.0 15.3 13.6 10.7 6.84 4.47 2.39 1.59 MEAN 0 3.02 5.76 7.46 10.1 1212.4 11.8 9.42 7.18 5.08 3.58 2.24 1.22 SD 0 1.53 2.45 2.53 2.03 2.452.61 2.81 2.77 2.27 1.48 0.943 0.556 0.408 % CV 0 50.7 42.5 33.9 20.120.4 21 23.8 29.4 31.6 29.1 26.3 24.8 33.4

TABLE 17 Hydrocodone Plasma Concentration (ng/mL) after administrationof two (2) Immediate-Release Hydrocodone 7.5 mg/Acetaminophen 500 mgtablets-Formulation C Time (hours) Subject −0.08 0.5 0.75 1 2 3 4 6 9 1218 24 30 36 1 0.00 40.6 41.6 45.4 32.1 26.3 22.7 15.2 9.95 6.08 2.581.20 0.585 0.00 2 0.00 44.3 50.7 40.1 28.6 23.3 20.2 15.6 9.46 6.08 2.961.68 0.872 0.00 3 0.00 17.6 42.3 42.6 37.8 35.4 31.2 21.0 13.0 7.79 3.121.77 0.685 0.00 4 0.00 21.2 43.3 36.5 26.9 23.5 20.7 15.4 9.39 5.09 2.271.17 0.523 0.00 5 0.00 37.4 39.3 36.1 27.9 22.4 18.1 14.1 7.91 4.98 2.371.07 0.546 0.00 6 0.00 3.17 8.67 16.3 17.5 16.9 13.8 11.3 6.52 4.22 1.710.703 0.00 0.00 7 0.00 0.900 6.76 14.7 18.3 17.1 14.1 9.66 5.52 3.321.21 0.00 0.00 0.00 8 0.00 2.97 13.7 22.2 32.4 28.8 24.2 18.3 10.9 6.462.17 1.02 0.00 0.00 9 0.00 50.0 39.3 33.7 24.2 20.1 17.0 13.0 6.84 4.011.47 0.565 0.00 0.00 10  0.00 0.627 14.8 25.2 22.4 17.3 16.5 10.9 5.903.15 1.05 0.00 0.00 0.00 11  0.00 8.46 13.3 29.3 31.3 24.8 21.0 14.09.43 6.04 2.62 1.14 0.00 0.00 12  0.00 30.6 44.4 44.4 40.0 30.8 29.119.9 11.3 6.86 3.15 1.47 0.634 0.00 13  0.00 3.73 12.2 17.9 19.1 19.816.3 13.9 8.72 5.43 2.51 0.706 0.00 0.00 14  0.00 18.0 29.7 35.3 30.726.6 23.4 16.1 9.20 6.24 2.60 1.27 0.556 0.00 MEAN 0.00 20.0 28.6 31.427.8 23.8 20.6 14.9 8.86 5.41 2.27 0.983 0.314 0.00 SD 0.00 17.7 16.010.6 6.93 5.48 5.21 3.26 2.15 1.36 0.676 0.541 0.336 0.00 % CV 0.00 88.555.9 33.8 24.9 23.0 25.3 21.9 24.3 25.1 29.8 55.0 107 0.00

TABLE 18 Hydrocodone Plasma Concentration (ng/mL) after administrationof one (1) Controlled-Release Hydrocodone Bitartrate 15 mgcapsule-Formulation D Time (hours) Subject −0.08 0.5 0.75 1 2 3 4 6 9 1218 24 30 36 1 0.00 1.76 4.07 5.17 8.33 9.72 11.1 14.0 13.6 11.7 8.786.14 3.91 1.97 2 0.00 2.76 4.83 5.13 6.17 10.4 10.6 13.5 11.8 10.1 6.573.71 2.57 1.34 3 0.00 2.91 4.25 6.01 10.1 12.3 12.0 14.8 13.5 11.4 7.404.16 2.65 1.46 4 0.00 1.69 5.93 6.26 8.29 8.37 8.06 10.5 8.91 8.70 4.582.61 1.63 0.536 5 0.00 0.616 2.74 4.47 8.58 9.16 8.60 10.1 8.66 6.644.72 2.57 2.05 0.986 6 0.00 0.663 2.40 4.87 7.50 10.1 11.7 13.0 11.58.30 5.38 3.88 2.39 1.25 7 0.00 0.00 1.55 2.32 4.61 6.38 7.22 7.41 6.754.82 3.10 1.72 0.984 0.578 8 0.00 1.26 3.03 5.15 7.26 8.80 8.81 9.349.07 9.28 6.81 3.31 1.93 1.25 9 0.00 3.36 3.63 6.38 8.31 8.04 8.20 9.558.28 6.49 3.72 2.25 1.92 0.901 10  0.00 0.692 2.91 2.95 5.11 6.09 7.377.11 6.33 5.67 3.76 2.76 1.43 0.573 11  0.00 1.11 2.87 3.28 6.82 9.6910.3 12.0 12.2 8.81 5.76 3.25 2.10 1.08 12  0.00 2.25 3.31 4.72 8.0311.4 11.2 12.1 11.0 9.75 5.64 3.51 2.71 1.34 13  0.00 0.00 1.29 2.715.51 6.67 8.92 8.44 7.13 7.01 3.99 2.41 1.04 0.858 14  0.00 1.02 2.944.53 8.82 10.5 11.7 14.1 13.0 10.2 6.37 3.56 1.93 1.61 MEAN 0.00 1.443.27 4.57 7.39 9.12 9.70 11.1 10.1 8.49 5.47 3.27 2.09 1.12 SD 0.00 1.061.23 1.31 1.57 1.86 1.71 2.57 2.55 2.11 1.61 1.08 0.754 0.419 % CV 0.0073.6 37.6 28.7 21.2 20.4 17.6 23.2 25.2 24.9 29.4 33.0 36.1 37.4

The pharmacokinetic parameters are set forth in Table 19 below:

TABLE 19 Parameter Mean^(a) % Ratio^(b,c) 90% Cl^(b) Ex. 1/ Ex. 1 IR Ex.IR Ex. Fasted Fasted Fasted Lower Upper AUC (0, last) 200.95 216.3593.36 86.96 100.23 (ng · hr/mL) Cmax (ng/mL) 13.16 33.37 39.48 35.2644.20 Tmax (hr) 4.07 1.32 208.11 257.17 357.80 W50 (hr) 13.41 4.67287.38 265.91 314.15 T½ (abs) (hr) 1.64 0.69 237.65 197.73 284.44 T½(elim) (hr) 6.44 3.09 208.78 184.43 234.20 Ex. 2/ Ex. 2 IR Ex. IR Ex.Fasted Fasted Fasted Lower Upper AUC (0, last) 201.57 216.35 93.21 86.82100.07 (ng · hr/mL) Cmax (ng/mL) 12.42 33.37 37.36 33.37 41.83 Tmax (hr)4.20 1.32 317.57 262.19 362.83 W50 (hr) 13.08 4.67 280.31 257.03 305.26T½ (abs) (hr) 1.57 0.69 227.91 183.84 270.55 T½ (elim) (hr) 7.86 3.09254.85 231.54 281.31 Ex. 3/ Ex. 3 IR. Ex. IR Ex. Fasted Fasted FastedLower Upper AUC (0, last) 194.40 216.35 90.28 84.09 96.92 (ng · hr/mL)Cmax (ng/mL) 10.93 33.37 32.69 29.20 36.60 Tmax (hr) 5.93 1.32 448.65398.87 499.51 W50 (hr) 16.30 4.67 349.21 328.68 376.92 T½ (abs) (hr)2.98 0.69 431.26 395.95 482.67 T½ (elim) (hr) 6.96 3.09 225.61 200.49250.26 ^(a)Geometric means for AUC (0, last) and Cmax and arithmeticmeans for Tmax, W50, T½ (abs), and T½ (elim). ^(b)Ratio and 90% Cl arebased on least square means. ^(c)Ratio (%): (Test mean/Reference mean) ×100, based on least square means

Example 8

Hydrocodone sustained release tablets were produced with the formula setforth in Table XX below:

TABLE XX Ingredient mg/tab kg/batch Hydrocodone bitartrate 15 15.0Dibasic calcium phosphate 31 31.0 Glyceryl behenate 10 10.0 Stearylalcohol 22 22.0 Microcrystalline cellulose 31 31.0 Magnesium stearate1.0 1.0 Opadry Purple YS-1-10371-A 5.0 5.0 Purified water N/A¹ 28.33¹115.0 mg 115.0 kg ¹Evaporates during processing and is not part offinished product.According to the following procedure:

-   1. Milling: Pass stearyl alcohol flakes through a mill.-   2. Blending: Mix The Hydrocodone bitartrate, Dibasic calcium    phosphate, Glyceryl behenate, Stearyl alcohol and Microcrystalline    cellulose with a suitable blender-   3. Extrusion: Continuously feed the blended material into a twin    screw extruder at an elevated temperature to soften and form an    extrudate.-   4. Cooling: Allow the extrudate to cool on a Conveyor.-   5. Milling: Pass the cooled extrudate through a mill to obtain a    suitable particle size granulation-   6. Blending: Blend the milled extrudate with the magnesium stearate.-   7. Compression: Compress the resultant granulation using a tablet    press.-   8. Coating: Prepare a film coating solution by dispersing the Opadry    in Purified Water and applying it to the tablet cores.

The tablets were then tested for dissolution using the followingprocedure:

-   1. Apparatus: USP Type I (basket), 100 rpm.-   2. Medium: 700 ml SGF (without enzymes) for first 55 minutes,    thereafter made 900 ml with phosphate buffer to pH 7.5.-   3. Sampling time: 1, 2, 4, 8, and 12 hours.-   4. Analytical: High Performance Liquid Chromatography.

The dissolution parameters are set forth in Table XXI below:

TABLE XXI Time (hrs) % Dissolved 1 22 2 37 4 58 8 84 12 99

Example 9

A 3 way crossover, pharmacokinetic comparison study of a single dose of15 mg Hydrocodone Controlled Release Tablets (Example 8) in Fed andFasted and of 15 mg Hydrocodone Immediate Release (2×7.5 mg tablets) wasgiven over two Q6H doses in fasted normal volunteers.The Cmax and Tmax were then obtained for Example 8 and an immediaterelease reference standard in a bioavailability study, as set forth inTable XXII and XXIII below:

TABLE XXII Pharmacokinetic data (Fasted State) Hydrocodone BitartrateCmax (ng/ml) IR reference product 43.16 (Dose adjusted) Cmax (ng/ml) CRproduct 17.87 Cmax (CR)/Cmax (IR) 41% Tmax (hr) IR reference product6.42 Tmax (hr) CR product 4.04

TABLE XXXIII Hydrocodone Hydrocodone Hydrocodone Bitartrate CRBitartrate CR Bitartrate IR Pharmacokinetic 15 mg Tablets 15 mg Tablets2 × 7.5 mg Tablets data (Fasted) (Fed) (Fasted) Cmax (ng/ml) 17.87 19.2321.58 C_(12 hour) 11.06 12.84 C_(12 hour)/Cmax 62% 67% Tmax (hr) 4.044.81 6.42 AUC 267.43 277.58 229.33

We claim:
 1. A twice-a-day solid oral controlled-release dosage formcomprising a gum and two types of multiparticulates, themultiparticulates collectively comprising from about 5 mg to about 60 mgof a pharmaceutically acceptable organic salt of hydrocodone, the gumand two types of multiparticulates compressed into a tablet, a firsttype of multiparticulates comprising microcrystalline cellulose and afirst portion of said 5 mg to 60 mg of the pharmaceutically acceptableorganic salt of hydrocodone, each multiparticulate individually coatedwith a controlled release coating comprising an acrylic polymer, asecond type of multiparticulates in the form of uncoated granules,spheroids, or pellets comprising a remaining portion of said 5 mg to 60mg of the pharmaceutically acceptable organic salt of hydrocodone, saiddosage form providing an in-vitro release of from 18% to about 42.5% byweight of hydrocodone from the dosage form at one hour when measured bythe USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid(SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml ofSimulated Intestinal Fluid (SIF) at 37° C., and, after a firstadministration to a human patient population, providing a plasmaconcentration of hydrocodone of at least 8 ng/ml at from about 2 toabout 8 hours after said administration and a plasma concentration ofhydrocodone of at least 6 ng/ml at about 12 hours after saidadministration, based on oral administration of a dosage form containing15 mg hydrocodone bitartrate, a mean C₁₂/C_(max) hydrocodone ratio of0.55 to 0.85, a mean T_(max) of hydrocodone from about 2 to 8 hours, anda therapeutic effect for about 12 hours.
 2. A twice-a-day solid oralcontrolled-release dosage form consisting essentially of an amount of abitartrate salt of hydrocodone equivalent to from about 5 mg to about 60mg of hydrocodone, a controlled release material selected from the groupconsisting of ethylcellulose, hydroxypropylmethylcellulose, and mixturesthereof, and additional pharmaceutically acceptable excipients selectedfrom the group consisting of lactose, glyceryl behenate, metalstearates, colorants, plasticizers, and mixtures thereof, the controlledrelease material and the additional pharmaceutically acceptableexcipients being in effective amounts such that the dosage form, after afirst administration to a human patient population, provides a meanC₁₂/C_(max) hydrocodone ratio of 0.55 to 0.85 and a therapeutic effectfor about 12 hours, wherein the dosage form is free from acrylicpolymers.
 3. The dosage form of claim 2, wherein said human populationis a fasted human patient population.
 4. The dosage form of claim 3,wherein the dosage form consists of said bitartrate salt of hydrocodoneand pharmaceutically acceptable excipients selected from the groupconsisting of ethylcellulose, hydroxypropylmethylcellulose, lactose,glyceryl behenate, metal stearates, colorants and plasticizers.